title: Sequestration of CDH1 by MAD2L2 prevents premature APC/C activation prior to anaphase onset.
abstract: The switch from activation of the anaphase-promoting complex/cyclosome (APC/C) by CDC20 to CDH1 during anaphase is crucial for accurate mitosis. APC/C(CDC20) ubiquitinates a limited set of substrates for subsequent degradation, including Cyclin B1 and Securin, whereas APC/C(CDH1) has a broader specificity. This switch depends on dephosphorylation of CDH1 and the APC/C, and on the degradation of CDC20. Here we show, in human cells, that the APC/C inhibitor MAD2L2 also contributes to ensuring the sequential activation of the APC/C by CDC20 and CDH1. In prometaphase, MAD2L2 sequestered free CDH1 away from the APC/C. At the onset of anaphase, MAD2L2 was rapidly degraded by APC/C(CDC20), releasing CDH1 to activate the dephosphorylated APC/C. Loss of MAD2L2 led to premature association of CDH1 with the APC/C, early destruction of APC/C(CDH1) substrates, and accelerated mitosis with frequent mitotic aberrations. Thus, MAD2L2 helps to ensure a robustly bistable switch between APC/C(CDC20) and APC/C(CDH1) during the metaphase-to-anaphase transition, thereby contributing to mitotic fidelity.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, England, UK.
authors.forename: Tamar
authors.initials: T
authors.lastname: Listovsky
authors.forename: Julian E
authors.initials: JE
authors.lastname: Sale
mesh_terms: D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D064199:Cdc20 Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D010766:Phosphorylation; D049468:Prometaphase; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D064199:Cdc20 Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; C577488:CDC20 protein, human; D064173:Anaphase-Promoting Complex-Cyclosome